Pyrido [2,1-a] isoquinoline derivatives

ABSTRACT

The present invention provides compounds of formula (I)  
                 
 
     wherein R 1 , R 2 , R 3  and R 4  are as indicated in the description, or a pharmaceutically acceptable salt thereof. The compounds are useful for the treatment of diseases which are associated with DPP-IV, such as diabetes, particularly non-insulin dependent diabetes mellitus, and impaired glucose tolerance.

BACKGROUND OF THE INVENTION

[0001] The enzyme dipeptidyl peptidase IV (EC.3.4.14.5, abbreviated inthe following as DPP-IV) is involved in the regulation of the activitiesof several hormones. In particular DPP-IV is degrading efficiently andrapidly glucagon like peptide 1 (GLP-1), which is one of the most potentstimulator of insulin production and secretion. Inhibiting DPP-IV wouldpotentiate the effect of endogenous GLP-1, and lead to higher plasmainsulin concentrations. In patients suffering from impaired glucosetolerance and type 2 diabetes mellitus, higher plasma insulinconcentration would moderate the dangerous hyperglycaemia andaccordingly reduce the risk of tissue damage. Consequently, DPP-IVinhibitors have been suggested as drug candidates for the treatment ofimpaired glucose tolerance and type 2 diabetes mellitus (e.g. Villhauer,WO98/19998). Other related state of the art can be found in WO 99/38501,DE 19616486, DE 19834591, WO 01/40180, WO 01/55105, U.S. Pat. No.6,110,949, WO 00/34241 and U.S. Pat. No. 6,011,155.

SUMMARY OF THE INVENTION

[0002] The present invention provides compounds of the formula (I)

[0003] wherein

[0004] R¹ is —C(O)—N(R⁵)R⁶ or —N(R⁵)R⁶;

[0005] R², R³ and R⁴ are each independently hydrogen, halogen, hydroxy,lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, loweralkoxy and lower alkenyl may optionally be substituted by loweralkoxycarbonyl, aryl or heterocyclyl;

[0006] R⁵ is hydrogen, lower alkyl, halogenated lower alkyl orcycloalkyl;

[0007] R⁶ is lower alkylsulfonyl, halogenated lower alkylsulfonyl,cycloalkylsulfonyl, lower alkylcarbonyl, halogenated loweralkylcarbonyl, cycloalkylcarbonyl; or

[0008] R⁵ and R⁶ together with the nitrogen atom to which they areattached form a 4-, 5-, 6- or 7-membered saturated or unsaturatednon-aromatic heterocyclic ring optionally containing a furtherheteroatom selected from nitrogen, oxygen and sulfur, said heterocyclicring being optionally mono-, di-, or tri-substituted, independently,with lower alkyl, halogenated lower alkyl, oxo, dioxo and/or cyano;

[0009] or a pharmaceutically acceptable salt thereof.

[0010] Compounds of the present invention are DPP-IV inhibitors thatlower plasma glucose levels, and are useful in the treatment ofnon-insulin dependent diabetes mellitus.

DETAILED DESCRIPTION OF THE INVENTION

[0011] We have found novel DPP-IV inhibitors that very efficiently lowerplasma glucose levels. Consequently, the compounds of the presentinvention are useful for the treatment and/or prophylaxis of diabetes,particularly non-insulin dependent diabetes mellitus, and/or impairedglucose tolerance, as well as other conditions wherein the amplificationof action of a peptide normally inactivated by DPP-IV gives atherapeutic benefit. Surprisingly, the compounds of the presentinvention can also be used in the treatment and/or prophylaxis ofobesity, inflammatory bowel disease, Colitis Ulcerosa, Morbus Crohn,and/or metabolic syndrome or β-cell protection. Furthermore, thecompounds of the present invention can be used as diuretic agents andfor the treatment and/or prophylaxis of hypertension.

[0012] Unexpectedly, the compounds of the present invention exhibitimproved therapeutic and pharmacological properties compared to otherDPP-IV inhibitors known in the art, such as e.g. in context withpharmacokinetics and bioavailability.

[0013] The present invention provides a compound of formula (I)

[0014] wherein

[0015] R¹ is —C(O)—N(R⁵)R⁶ or —N(R⁵)R⁶;

[0016] R², R³ and R⁴ are each independently hydrogen, halogen, hydroxy,lower alkyl, lower alkoxy, lower alkenyl, substituted lower alkyl,substituted lower alkoxy, or substituted lower alkenyl, whereinsubstituted lower alkyl, substituted lower alkoxy and substituted loweralkenyl are lower alkyl, lower alkoxy and lower alkenyl, respectively,which are independently substituted by a group selected from the groupconsisting of lower alkoxycarbonyl, aryl and heterocyclyl;

[0017] R⁵ is hydrogen, lower alkyl, halogenated lower alkyl orcycloalkyl;

[0018] R⁶ is lower alkylsulfonyl, halogenated lower alkylsulfonyl,cycloalkylsulfonyl, lower alkylcarbonyl, halogenated loweralkylcarbonyl, or cycloalkylcarbonyl; or

[0019] R⁵ and R⁶ together with the nitrogen atom to which they areattached form a 4-, 5-, 6- or 7-membered saturated or unsaturatednon-aromatic heterocyclic ring optionally containing a furtherheteroatom selected from nitrogen, oxygen and sulfur, said heterocyclicring being optionally mono-, di-, or tri-substituted, independently,with a group selected from the group consisting of lower alkyl,halogenated lower alkyl, oxo, dioxo and cyano;

[0020] or a pharmaceutically acceptable salt thereof.

[0021] Unless otherwise indicated, the following definitions are setforth to illustrate and define the meaning and scope of the variousterms used to describe the invention herein. In this specification theterm “lower” is used to mean a group consisting of one to six,preferably of one to four carbon atom(s).

[0022] The term “halogen” refers to fluorine, chlorine, bromine andiodine, with fluorine, bromine and chlorine being preferred. Mostpreferred halogen is fluorine.

[0023] The term “alkyl”, alone or in combination with other groups,refers to a branched or straight-chain monovalent saturated aliphatichydrocarbon radical of one to twenty carbon atoms, preferably one tosixteen carbon atoms, more preferably one to ten carbon atoms.

[0024] The term “lower alkyl”, alone or in combination with othergroups, refers to a branched or straight-chain monovalent alkyl radicalof one to six carbon atoms, preferably one to four carbon atoms. Thisterm is further exemplified by radicals such as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, 3-methylbutyl,n-hexyl, 2-ethylbutyl and the like. Preferable lower alkyl residues aremethyl and ethyl, with methyl being especially preferred.

[0025] The term “halogenated lower alkyl” refers to a lower alkyl groupwherein at least one of the hydrogens of the lower alkyl group isreplaced by a halogen atom, preferably fluoro or chloro, most preferablyfluoro. Among the preferred halogenated lower alkyl groups aretrifluoromethyl, difluoromethyl, fluoromethyl and chloromethyl, withfluoromethyl being especially preferred.

[0026] The term “alkoxy” refers to the group R′—O—, wherein R′ is alkyl.The term “lower-alkoxy” refers to the group R′—O—, wherein R′ islower-alkyl. Examples of lower alkoxy groups are e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy beingespecially preferred.

[0027] The term “lower alkoxycarbonyl” refers to the group R′—O—C(O)—,wherein R′ is lower alkyl.

[0028] The term “aryl” refers to an aromatic monovalent mono- orpolycarbocyclic radical, such as phenyl or naphthyl, preferably phenyl,which may optionally be mono-, di- or tri-substituted, independently, bylower alkyl, lower alkoxy, halo, cyano, azido, amino, di-lower alkylamino or hydroxy.

[0029] The term “cycloalkyl” refers to a monovalent carbocyclic radicalof three to six, preferably three to five carbon atoms. This term isfurther exemplified by radicals such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, with cyclopropyl and cyclobutyl beingpreferred. Such cycloalkyl residues may optionally be mono-, di- ortri-substituted, independently, by lower alkyl or by halogen.

[0030] The term “heterocyclyl” refers to a 5- or 6-membered aromatic orsaturated N-heterocyclic residue, which may optionally contain a furthernitrogen or oxygen atom, such as imidazolyl, pyrazolyl, thiazolyl,pyridyl, pyrimidyl, morpholino, piperazino, piperidino or pyrrolidino,preferably pyridyl, thiazolyl or morpholino. Such heterocyclic rings mayoptionally be mono-, di- or tri-substituted, independently, by loweralkyl, lower alkoxy, halo, cyano, azido, amino, di-lower alkyl amino orhydroxy. Preferable substituent is lower alkyl, with methyl beingpreferred.

[0031] The term “a 4-, 5-, 6- or 7-membered saturated or unsaturatednon-aromatic heterocyclic ring optionally containing a furtherheteroatom selected from nitrogen, oxygen and sulfur” refers to anon-aromatic heterocyclic ring, said heterocyclic ring being optionallymono-, di-, or tri-substituted, independently, with lower alkyl,halogenated lower alkyl, oxo, dioxo and/or cyano. Such saturatedheterocyclic rings are for example pyrrolidinyl, piperidinyl, azepanyl,[1,2]thiazinanyl, [1,3]oxazinanyl, oxazolidinyl, thiazolidinyl orazetidinyl. Examples of such unsaturated heterocyclic rings are5,6-dihydro-1H-pyridin-2-one, pyrrolinyl, tetrahydropyridine ordihydropyridine.

[0032] The term “pharmaceutically acceptable salts” embraces salts ofthe compounds of formula (I) with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,fumaric acid, succinic acid, tartaric acid, methanesulphonic acid,salicylic acid, p-toluenesulphonic acid and the like, which are nontoxic to living organisms. Preferred salts with acids are formates,maleates, citrates, hydrochlorides, hydrobromides and methanesulfonicacid salts, with hydrochlorides being especially preferred.

[0033] In one embodiment of the present invention, R¹ is —C(O)—N(R⁵)R⁶.In another embodiment, R¹ is —N(R⁵)R⁶.

[0034] In another embodiment, R², R³ and R⁴ are each independentlyhydrogen, hydroxy, lower alkoxy, or lower alkoxy substituted by aryl, byheterocyclyl or by lower alkoxycarbonyl. Preferable aryl residues in R²,R³ and R⁴ are phenyl or phenyl substituted by di-lower alkylamino or bycyano. Preferable heterocyclyl residues in R², R³ and R⁴ are morpholino,pyridyl, thiazolyl or thiazolyl substituted by lower alkyl. Preferablelower alkoxycarbonyl residues in R², R³ and R⁴ are methoxycarbonly andethoxycarbonly.

[0035] In another embodiment, R², R³ and R⁴ are each independentlyhydrogen, hydroxy or lower alkoxy.

[0036] In one preferable embodiment, residue R² is lower alkoxy,preferably methoxy, hydrogen or hydroxy. Most preferable residue R² ismethoxy.

[0037] In another preferable embodiment, residue R³ is lower alkoxy,with methoxy, ethoxy, propoxy, n-butoxy and isobutoxy being preferred,or hydrogen or hydroxy. Most preferable residue R³ is methoxy orhydroxy, with methoxy being especially preferred.

[0038] In another preferable embodiment, residue R⁴ is lower alkoxy,preferably methoxy, hydrogen or hydroxy. Most preferable residue R⁴ ishydrogen.

[0039] In one embodiment, R⁵ is hydrogen, lower alkyl, halogenated loweralkyl or cycloalkyl. Preferable lower alkyl residues in R⁵ are methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl, withmethyl and ethyl being especially preferred. Preferable halogenatedlower alkyl residues R⁵ are fluoromethyl, 2-fluoroethyl and3-fluoropropyl, with fluoromethyl being especially preferred. Preferredcycloalkyl residues R⁵ are unsubstituted cyclopropyl and unsubstitutedcyclobutyl. Preferably, R⁵ is hydrogen, lower alkyl such as methyl orhalogenated lower alkyl such as fluoromethyl.

[0040] In one embodiment, R⁶ is lower alkylsulfonyl, halogenated loweralkylsulfonyl, cycloalkylsulfonyl, lower alkylcarbonyl, halogenatedlower alkylcarbonyl, cycloalkylcarbonyl. Preferable lower alkylsulfonylresidues R⁶ are methylsulfonyl, ethylsulfonyl and propylsulfonyl, withmethylsulfonyl and ethylsulfonyl being especially preferred. Preferablelower alkylcarbonyl residues R⁶ are methylcarbonyl, ethylcarbonyl andpropylcarbonyl, with methylcarbonyl and ethylcarbonyl being especiallypreferred. Preferable halogenated lower alkylsulfonyl residues R⁶ areethylsulfonyl and propylsulfonyl. Preferable halogenated loweralkylcarbonyl residues R⁶ are pentafluoroethylsulfonyl and2,2,2-trifluoroethylsulfonyl. Preferable cycloalkylsulfonyl residues R⁶are cydopropylsulfonyl and cyclobutylsulfonyl. Preferablecycloalkylcarbonyl residues R⁶ are cyclopropylcarbonyl andcyclobutylcarbonyl.

[0041] In a preferable embodiment, R⁶ is lower alkylsulfonyl, preferablyethylsulfonyl, or lower alkylcarbonyl, preferably ethylcarbonyl, orcycloalkylcarbonyl, preferably cyclopropylcarbonyl.

[0042] In another embodiment, R⁵ and R⁶ together with the nitrogen atomto which they are attached form a 4-, 5-, 6- or 7-membered saturated orunsaturated heterocyclic ring optionally containing a further heteroatomselected from nitrogen, oxygen and sulfur, preferably sulfur, saidheterocyclic ring being optionally mono-, di-, or tri-substituted,preferably mono- or di-substituted, independently, with lower alkyl suchas methyl or ethyl, halogenated lower alkyl such as fluoromethyl, oxo,dioxo and/or cyano.

[0043] In still another embodiment, R⁵ and R⁶ together with the nitrogenatom to which they are attached form a 4-, 5-, 6- or 7-memberedsaturated or unsaturated heterocyclic ring optionally containing asulfur atom or an oxygen atom as a further heteroatom in the ring, saidheterocyclic ring being optionally mono- or di-substituted,independently, with lower alkyl such as methyl or ethyl, halogenatedlower alkyl such as fluoromethyl, oxo, dioxo and/or cyano.

[0044] In a preferred embodiment, R⁵ and R⁶ together with the nitrogenatom to which they are attached are pyrrolidine, pyrrolidin-2-one,4-methyl-pyrrolidin-2-one, 4-ethyl-pyrrolidin-2-one,3-methyl-pyrrolidin-2-one, 5-methyl-pyrrolidin-2-one,4-fluoro-methyl-pyrrolidin-2-one, pyrrolidine-2-carbonitrile,piperidine, piperidin-2-one, 4-methyl-piperidin-2-one,5-methyl-piperidin-2-one, 5,6-dihydro-1H-pyridin-2-one,thiazolidin-3-yl, 1,1-dioxo-1,2-thiazolidin-2-yl,1,1-dioxo[1,2]thiazinan-2-yl, azetidine, azepan-2-one, oxazolidin-2-one,5-methyl-oxazolidin-2-one, 5-fluoromethyl-oxazolidin-2-one, oroxazinan-2-one. Most preferably, R⁵ and R⁶ together with the nitrogenatom to which they are attached are thiazolidin-3-yl, piperidin-2-one,4-methyl-pyrrolidin-2-one, 4-fluoromethyl-pyrrolidin-2-one,5,6-dihydro-1H-pyridin-2-one, 5-methyl-piperidin-2-one,5-methyl-oxazolidin-2-one and 1,1-dioxo[1,2]thiazinan-2-yl.

[0045] In still another embodiment, the present invention is directed tocompounds of formula I, wherein R¹ is —C(O)—N(R⁵)R⁶ or —N(R⁵)R⁶; R² islower alkoxy such as methoxy; R³ is lower alkoxy such as methoxy; and R⁴is hydrogen; and R⁵ and R⁶ together with the nitrogen atom to which theyare attached form a 4-, 5-, 6- or 7-membered saturated or unsaturatedheterocyclic ring optionally containing a sulfur atom as a furtherheteroatom in the ring, said heterocyclic ring being optionally mono- ordi-substituted, independently, with lower alkyl such as methyl or ethyl,halogenated lower alkyl such as fluoromethyl, oxo, dioxo and/or cyano.

[0046] Preferred compounds of general formula (I) are those selectedfrom the group consisting of:

[0047](RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-pyrrolidin-1-yl-methanone,

[0048](RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-thiazolidin-3-yl-methanone,

[0049](RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azetidin-1-yl-methanone,

[0050](SS)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carbonyl)-pyrrolidine-2-carbonitrile,

[0051]1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one,

[0052](−)—(S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one,

[0053](+)—(R,R,R)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one,

[0054]1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-piperidin-2-one,

[0055](RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-pyrrolidin-2-one,

[0056]1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0057]1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-ethyl-pyrrolidin-2-one,

[0058](RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5,6-dihydro-1H-pyridin-2-one,

[0059]1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azepan-2-one,

[0060](RS,RS,RS)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,

[0061] (RS,RS,RS)-3-(1,1-dioxo[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,

[0062](S,S,S)-3-(1,1-dioxo-[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,

[0063](SR)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0064](RS,RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0065] (R)—1-((S,S,S)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0066](S)-1-((R,R,R)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0067](S,S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0068](R,R,R,R)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0069]1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,

[0070]1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-piperidin-2-one,

[0071](RS,RS,RS)—N-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-propionamide,

[0072](RS,RS,RS)—N-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-butyramide,

[0073] cyclopropanecarboxylic acid ((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-amide,

[0074](SR)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

[0075](RS,RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,

[0076] (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,

[0077](R)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,

[0078](S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-onedihydrochloride,

[0079] (R)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-onedihydrochloride,

[0080]3-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-oxazolidin-2-one,

[0081] 3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-[1,3]oxazinan-2-one,

[0082] 1-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-pyrrolidin-2-one,

[0083] 3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-fluoromethyl-oxazolidin-2-one,

[0084] 1-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-3-methyl-pyrrolidin-2-one,

[0085] 3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-oxazolidin-2-one,

[0086] and pharmaceutically acceptable salts thereof.

[0087] Especially preferred compounds of general formula (I) are thoseselected from the group consisting of:

[0088](RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-thiazolidin-3-yl-methanone,

[0089](−)—(S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one,

[0090]1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0091](RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5,6-dihydro-1H-pyridin-2-one,

[0092](S,S,S)-3-(1,1-dioxo-[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,

[0093](R)—-((S,S,S)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0094](S,S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one,

[0095]1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-piperidin-2-one,

[0096] (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,

[0097](R)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,

[0098] 3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-oxazolidin-2-one,

[0099] and pharmaceutically acceptable salts thereof.

[0100] The compounds of formula I have three or more asymmetric carbonatoms and can exist in the form of optically pure enantiomers, mixturesof diastereomers, racemates, or mixtures of diasteroisomeric racemates.The invention embraces all of these forms.

[0101] In one preferable embodiment, R¹, the amino group in position 2and the hydrogen in position 11b of the pyrido[2,1-a]isoquinolinebackbone are all in S configuration, i.e.

[0102] In another preferable embodiment, R¹, the amino group in position2 and the hydrogen in position 11b of the pyrido[2,1-a]isoquinolinebackbone are all in R configuration, i.e.

[0103] It will be appreciated, that the compounds of general formula (I)in this invention may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundin vivo.

[0104] The present invention also relates to a process for themanufacture of compounds of formula I. The compounds of the presentinvention can be prepared as below:

[0105] In the following reaction schemes (Scheme 1 to 6) substituentsR¹, R², R³, R⁴, R⁵ and R⁶ have the meanings as defined above, unlessotherwise indicated.

[0106] Compounds of general formula I are synthesized from carbamate Aby methods known in the art, preferably using hydrogen chloride indioxane or trifluoroacetic acid in dichloromethane when P is Boc.Carbamate A can be obtained from N-benzylcarbamate A′ by methods knownin the art, preferably by hydrogenation at a pressure of about 3 bar, inthe presence of palladium on activated charcoal, in a solvent such asethanol (Scheme 1).

[0107] P is a suitable amino protecting group such as benzyloxycarbonyl(Z), allyloxycarbonyl (Aloc), and, preferably, tert-butoxycarbonyl(Boc).

[0108] Converting of a compound of formula A into a compound of formulaI is done by cleaving the amino protecting group. The cleavage of theamino protecting group can be done by conventional methods as they arefor example described in P. Kocienski, Protecting groups, Thieme VerlagStuttgart New York 1994, pages 192-201. Preferably, cleavage of theamino protecting group is done under acidic conditions. The preferredcarbamate amino protecting group is tert-butoxycarbonyl which can becleaved by acidolysis with strong acids such as hydrogen chloride ortrifluoroacetic acid, or with Lewis acids. Preferably, it is cleavedwith 4M hydrogen chloride solution in dioxane. Alternatively, the aminoprotecting group is cleaved by catalytic hydrogenation under conditionswell-known to the skilled person.

[0109] The synthesis of amide derivatives A1 is outlined in Scheme 2 andstarts with the β-ketoester B (R^(a)=methyl or ethyl). Compounds offormula B are well known in the art (e.g., Helv. Chim. Acta 1958, 41,119). Reaction of B with ammonium acetate in a solvent such as methanolproduces the β-enamino-ester C, which is reduced, preferably with sodiumborohydride/trifluoroacetic acid, to the corresponding theβ-amino-ester. The amino group is optionally benzylated and thenconverted to the tert-butyl carbamate of formula D. The ester group of Dis hydrolyzed using a base, preferably potassium hydroxide or sodiumhydroxide in a water/tetrahydrofuran mixture, to yield the acid E.Compound E is reacted with an appropriate amine in the presence of asuitable coupling agent, e.g.,O-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), and a base, e.g., N-ethyldiisopropylamine,to yield amide A2.

[0110] R^(a) methyl or ethyl, R^(p)═H or PhCH₂.

[0111] The synthesis of lactam or sultam derivatives A2 starts fromcarboxylic acid E and is outlined in Scheme 3. Acid E is converted intocarbamate F through a Curtius rearrangement, using methods known in theart (e.g., Tetrahedron 1974, 30, 2157 or Tetrahedron Lett. 1984, 25,3515). Amine G is produced from carbamate F via standard methods (H₂,Pd—C, acetic acid in the case of R^(b)=benzyl; Bu₄NF/THF, Et₄NF/CH₃CN,or CsF/DMF in the case of R^(b)=Me₃SiCH₂CH₂). Amine G is reacted withacid chloride, sulfonyl chloride, or chloroformate H in the presence ofa base (e.g., triethylamine) to afford amide or sulfonamide K.Alternatively, amide K is obtained from G by reaction with lactone J,followed by conversion of the newly formed hydroxyl into a leavinggroup, using methods known in the art. Finally, cyclisation of K using abase, e.g., sodium hydride, in a solvent such as N,N-dimethylformamide,optionally in the presence of sodium iodide, leads to A2.

[0112] R^(b)=Me₃SiCH₂CH₂ or PhCH₂; R^(p)=H or PhCH₂; W═C or S(═O); Xleaving group, e.g., Cl, Br, or OTs.

[0113] Unsaturated lactams of the formula A3 are synthesized from amineG according to Scheme 4. Thus, alkylation of G with alkenyl halide L (inthe presence of a base, e.g., triethylamine), followed by acylation (inthe presence of a base, e.g., triethylamine) with acyl halide M, affordsamide N. Compound N is subjected to ring-closing metathesis (Acc. Chem.Res. 2001, 34, 18), using a ruthenium catalyst, e.g.,bis(tricyclohexylphosphine)-benzylideneruthenium(IV)dichloride, andoptionally a Lewis acid, e.g., tetraisopropyl-orthotitanate, to affordA3.

[0114] R^(p)=H or PhCH₂; X=leaving group, e.g., Cl or Br.

[0115] Amides and sulfonamides of formula A4 are prepared according toScheme 5, by treatment of amine G (in the case of R⁵=H) or P (in thecase of R⁵≠H) with appropriate acid chlorides or sulfonyl chlorides. Thetransformation of G into secondary amine P is performed, e.g., byalkylation, reductive alkylation, or acylation and subsequent reduction,using methods known in the art.

[0116] R^(p)=H or PhCH₂.

[0117] Ketoester B can be produced from1,2,3,4-tetrahydro-1-isoquinolineacetate Q via diester intermediate R(Scheme 6), according to literature procedures (e.g., Helv. Chim. Acta1958, 41, 119). Compounds of formula Q are well known in the art and canbe produced by a wide variety of methods (e.g., Synthesis 1987, 474 andreferences cited therein).

[0118] R^(a)=methyl or ethyl.

[0119] The compounds of formula I have three or more asymmetric carbonatoms and can exist in the form of optically pure enantiomers, mixturesof diastereomers, racemates, or mixtures of diasteroisomeric racemates.The optically active forms can be obtained for example by fractionalcrystallization or asymmetric chromatography (chromatography with achiral adsorbent or eluant) of the racemates of the compounds of formulaI. Likewise, synthetic precursors of the compounds of formula I can beseparated into the pure enantiomers. In particular, the optically pureforms of 1,2,3,4-tetrahydro-1-isoquinolineacetate (Q*) can be used as astarting material for the synthesis of optically pure compounds offormula I. Optically pure forms of Q are well known in the literatureand can be produced from the racemates by fractional crystallizationusing chiral resolving agents, e.g., tartranilic acids, as described byMontzka et al. (U.S. Pat. No. 3,452,086). Alternatively, the pureenantiomers Q* can be synthesized from achiral precursors, e.g., byaddition of ketene silyl acetals S to nitrones of formula T in thepresence of chiral Lewis acids, followed by reduction of theintermediate U with zinc, as described by Murahashi and co-workers (J.Am. Chem. Soc. 2002, 124, 2888, Scheme 7).

[0120] R^(a)=methyl or ethyl.

[0121] The invention further relates to compounds of formula (I) asdefined above, when manufactured according to a process as definedabove.

[0122] As described above, the compounds of formula (I) of the presentinvention can be used as medicaments for the treatment and/orprophylaxis of diseases which are associated with DPP-IV such asdiabetes, particularly non-insulin dependent diabetes mellitus, impairedglucose tolerance, inflammatory bowel disease, Colitis Ulcerosa, MorbusCrohn, obesity, and/or metabolic syndrome or β-cell protection,preferably non-insulin dependent diabetes mellitus and/or impairedglucose tolerance. Furthermore, the compounds of the present inventioncan be used as diuretic agents or for the treatment and/or prophylaxisof hypertension.

[0123] The invention therefore also relates to pharmaceuticalcompositions comprising a compound as defined above and apharmaceutically acceptable carrier and/or adjuvant.

[0124] Further, the invention relates to compounds as defined above foruse as therapeutic active substances, particularly as therapeutic activesubstances for the treatment and/or prophylaxis of diseases which areassociated with DPP-IV such as diabetes, particularly non-insulindependent diabetes mellitus, impaired glucose tolerance, inflammatorybowel disease, Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolicsyndrome or β-cell protection, preferably for use as therapeutic activesubstances for the treatment and/or prophylaxis of non-insulin dependentdiabetes mellitus and/or impaired glucose tolerance. Furthermore, theinvention relates to compounds as defined above for use as diureticagents or for use as therapeutic active substances for the treatmentand/or prophylaxis of hypertension.

[0125] In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which are associated withDPP-IV such as diabetes, particularly non-insulin dependent diabetesmellitus, impaired glucose tolerance, inflammatory bowel disease,Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome orβ-cell protection, preferably for the treatment and/or prophylaxis ofnon-insulin dependent diabetes mellitus and/or impaired glucosetolerance, which method comprises administering a compound as definedabove to a human being or animal. Furthermore, the invention relates toa method for the treatment and/or prophylaxis as defined above, whereinthe disease is hypertension or wherein a diuretic agent has a beneficialeffect. The invention further relates to the use of compounds as definedabove for the treatment and/or prophylaxis of diseases which areassociated with DPP-IV such as diabetes, particularly non-insulindependent diabetes mellitus, impaired glucose tolerance, inflammatorybowel disease, Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolicsyndrome or β-cell protection, preferably for the treatment and/orprophylaxis of non-insulin dependent diabetes mellitus and/or impairedglucose tolerance. Furthermore, the invention relates to the use asdefined above, wherein the disease is hypertension or to the use asdiuretic agent.

[0126] In addition, the invention relates to the use of compounds asdefined above for the preparation of medicaments for the treatmentand/or prophylaxis of diseases which are associated with DPP-IV such asdiabetes, particularly non-insulin dependent diabetes mellitus, impairedglucose tolerance, inflammatory bowel disease, Colitis Ulcerosa, MorbusCrohn, obesity, and/or metabolic syndrome or β-cell protection,preferably for the treatment and/or prophylaxis of non-insulin dependentdiabetes mellitus and/or impaired glucose tolerance. Such medicamentscomprise a compound as defined above. Furthermore, the invention relatesto the use as defined above, wherein the disease is hypertension or theuse for the preparation of diuretic agents.

[0127] In context with the methods and uses defined above, the followingdiseases relate to a preferred embodiment: diabetes, particularlynon-insulin dependent diabetes mellitus, impaired glucose tolerance,obesity, and/or metabolic syndrome or β-cell protection, preferablynon-insulin dependent diabetes mellitus and/or impaired glucosetolerance.

[0128] The compounds of formula (I) can be manufactured by the methodsgiven below, by the methods given in the Examples or by analogousmethods. Appropriate reaction conditions for the individual reactionsteps are known to the person skilled in the art. Starting materials areeither commercially available or can be prepared by methods analogous tothe methods given below or in the Examples or by methods known in theart.

[0129] The following tests were carried out in order to determine theactivity of the compounds of formula I.

[0130] Activity of DPP-IV inhibitors are tested with natural humanDPP-IV derived from a human plasma pool or with recombinat human DPP-IV.Human citrate plasma from different donors is pooled, filterted througha 0.2 micron membrane under sterile conditions and aliquots of 1 ml areshock frozen and stored at −120° C. until used. In the colorimetricDPP-IV assay 5 to 10 μl human plasma and in the fluorometric assay 1.0μl of human plasma in a total assay volume of 100 μl is used as anenzyme source. The cDNA of the human DPP-IV sequence of amino acid 31-to 766, restricted for the N-terminus and the transmembrane domain, iscloned into Pichia pastoris. Human DPP-IV is expressed and purified fromthe culture medium using conventional column chromatography includingsize exclusion and anion and cation chromatography. The purity of thefinal enzyme preparation of Coomassie blue SDS-PAGE is >95%. In thecalorimetric DPP-IV assay 20 ng rec.-h DPP-IV and in the fluorometricassay 2 ng rec-h DPP-IV in a total assay volume of 100 μl is used as anenzyme source.

[0131] In the fluorogenic assayAla-Pro-7-amido-4-trifluoromethylcoumarin (Calbiochem No 125510) is usedas a substrate. A 20 mM stock solution in 10% DMF/H₂O is stored at −20°C. until use. In IC₅₀ determinations a final substrate concentration of50 μM is used. In assays to determine kinetic parameters as K_(m),V_(max), K_(i), the substrate concentration is varied between 10 μM and500 μM.

[0132] In the colorimetric assay H-Ala-Pro-pNA.HCl (Bachem L-1115) isused as a substrate. A 10 mM stock solution in 10% MeOH/H₂O is stored at−20° C. until use. In IC₅₀ determinations a final substrateconcentration of 200 μM is used. In assays to determine kineticparameters as K_(m), V_(max), K_(i), the substrate concentration isvaried between 100 μM and 2000 μM. Fluorescence is detected in a PerkinElmer Luminescence Spectrometer LS 50B at an excitation wavelength of400 nm and an emission wavelength of 505 nm continuously every 15seconds for 10 to 30 minutes. Initial rate constants are calculated bybest fit linear regression.

[0133] The absorption of pNA liberated from the colorimetric substrateis detected in a Packard SpectraCount at 405 nm continuosly every 2minutes for 30 to 120 minutes. Initial rate constants are calculated bybest fit linear regression.

[0134] DPP-IV activity assays are performed in 96 well plates at 37° C.in a total assay volume of 100 μl. The assay buffer consists of 50 mMTris/HCl pH 7.8 containing 0.1 mg/ml BSA and 100 mM NaCl. Test compoundsare solved in 100% DMSO, diluted to the desired concentration in 10%DMSO/H₂O. The final DMSO concentration in the assay is 1% (v/v). At thisconcentration enzyme inactivation by DMSO is <5%. Compounds are with (10minutes at 37° C.) and without preincubation with the enzyme. Enzymereactions are started with substrate application followed by immediatemixing.

[0135] IC₅₀ determinations of test compounds are calculated bynon-linear best fit regression of the DPP-IV inhibition of at least 5different compound concentrations. Kinetic parameters of the enzymereaction are calculated at at least 5 different substrate concentrationsand at least 5 different test compound concentrations.

[0136] The compounds of the present invention exhibit IC₅₀ values of 0.1nM to 10 μM, more preferably of 0.1-100 nM, as shown in the followingtable: Example IC₅₀ [μM] 2 0.041 6 0.023 10 0.0093 12 0.033 16 0.131

[0137] The compounds of formula I and/or their pharmaceuticallyacceptable salts can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or tropicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils. Oral administration is preferred.

[0138] The production of the pharmaceutical preparations can be effectedin a manner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

[0139] Suitable carrier materials are not only inorganic carriermaterials, but also organic carrier materials. Thus, for example,lactose, corn starch or derivatives thereof, talc, stearic acid or itssalts can be used as carrier materials for tablets, coated tablets,dragées and hard gelatine capsules. Suitable carrier materials for softgelatine capsules are, for example, vegetable oils, waxes, fats andsemi-solid and liquid polyols (depending on the nature of the activeingredient no carriers might, however, be required in the case of softgelatine capsules). Suitable carrier materials for the production ofsolutions and syrups are, for example, water, polyols, sucrose, invertsugar and the like. Suitable carrier materials for injection solutionsare, for example, water, alcohols, polyols, glycerol and vegetable oils.Suitable carrier materials for suppositories are, for example, naturalor hardened oils, waxes, fats and semi-liquid or liquid polyols.Suitable carrier materials for topical preparations are glycerides,semi-synthetic and synthetic glycerides, hydrogenated oils, liquidwaxes, liquid paraffins, liquid fatty alcohols, sterols, polyethyleneglycols and cellulose derivatives. Usual stabilizers, preservatives,wetting and emulsifying agents, consistency-improving agents,flavour-improving agents, salts for varying the osmotic pressure, buffersubstances, solubilizers, colorants and masking agents and antioxidantscome into consideration as pharmaceutical adjuvants.

[0140] The dosage of the compounds of formula I can vary within widelimits depending on the disease to be controlled, the age and theindividual condition of the patient and the mode of administration, andwill, of course, be fitted to the individual requirements in eachparticular case. For adult patients a daily dosage of about 1 to 1000mg, especially about 1 to 100 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g. in 1 to 3 dosage units.

[0141] The pharmaceutical preparations conveniently contain about 1-500mg, preferably 1-100 mg, of a compound of formula I.

[0142] The following Examples serve to illustrate the present inventionin more detail. They are, however, not intended to limit its scope inany manner.

EXAMPLES

[0143] Abbreviations: MS=mass spectrometry, aq.=aqueous, r.t.=roomtemperature, THF=tetrahydrofuran, NMR=nuclear magnetic resonancespectroscopy, DMF=dimethylformamide, DMSO=dimethylsulfoxide,ISP=ionspray.

Example 1(RS,RS,RS)-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-pyrrolidin-1-yl-methanone

[0144]

[0145] a)2-Amino-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid Ethyl Ester

[0146] A mixture of9,10-dimethoxy-2-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid ethyl ester (Helv. Chim. Acta 1958, 41, 119; 4.00 g, 12.0 mmol) andammonium acetate (13.9 g, 180 mmol) in methanol was stirred 5 h at roomtemperature. After evaporation of the solvent the residue waspartitioned between dichloromethane and 1 M aq. sodium hydroxidesolution. The organic layer was dried (MgSO₄), and triturated withheptane to afford the title compound (3.71 g, 93%). Off-white solid, MS(ISP) 333.2 (M+H)⁺.

[0147] b)(RS,RS,RS)-2-tert-Butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic Acid Ethyl Ester

[0148] Trifluoroacetic acid (120 mL) was added at 0° C. to a solution of2-amino-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylicacid ethyl ester (6.90 g, 20.8 mmol) in tetrahydrofuran (60 mL), thenafter 30 min the homogeneous solution was treated with sodiumborohydride (1.64 g, 41.5 mmol) and stirred for another 40 min. Thereaction mixture was concentrated in vacuo and the residue partitionedbetween 2 M aq. sodium hydroxide solution and dichloromethane. Theorganic layer was washed with brine, dried (MgSO₄) and evaporated. Theresidue was dissolved in dichloromethane (80 mL), and a solution ofdi-tert-butyl-dicarbonate (4.98 g, 22.8 mmol) in dichloromethane (50 mL)was added at r.t. The solution was stirred overnight at r.t.,concentrated, and the residue was triturated in heptane to afford thetitle compound (7.44 g, 83%). Light yellow solid, MS (ISP) 435.4 (M+H)⁺.

[0149] c)(RS,RS,RS)-2-tert-Butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic Acid

[0150] Potassium hydroxide pellets (86%, 4.47 g, 68.5 mmol) was added toa suspension of(RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid ethyl ester (7.44 g, 17.1 mmol) in tetrahydrofuran/water 1:1 (140mL). After heating 5 h at reflux, the mixture was concentrated in vacuo.The residue was taken up in 1M aq. potassium phosphate buffer (pH 6.85)and dichloromethane, and ethanol was added until a clear two-phasemixture was obtained. The organic layer was separated, washed with brineand evaporated to afford the title compound (6.91 g, 99%). Light yellowsolid, MS (ISP) 405.3 (M−H)⁻.

[0151] d)(RS,RS,RS)-[9,10-Dimethoxy-3-(pyrrolidine-1-carbonyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0152] N-Ethyldiisopropylamine (96 mg, 0.74 mmol) andO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 103 mg, 0.27 mmol) were added at r.t. to asuspension of(RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (100 mg, 0.25 mmol) in N,N,dimethylformamide (2 mL), then after 45min pyrrolidine (19 mg, 0.27 mmol) was added. The homogeneous solutionwas stirred 90 min at r.t., then partitioned between hexane/ethylacetate 1:1 and water. The organic layer was washed with brine, dried(MgSO₄), and evaporated, and the residue chromatographed (SiO₂,CH₂Cl₂/MeOH/NH₄OH 80:1:0.2) to produce the title compound (58 mg, 51%).Light yellow solid, MS (ISP) 460.5 (M+H)⁺.

[0153] e) (RS,RS,RS)—(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-pyrrolidin-1-yl-methanone

[0154] A solution of(RS,RS,RS)-[9,10-dimethoxy-3-(pyrrolidine-1-carbonyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (55 mg, 0.12mmol) in hydrogen chloride solution (4 M in dioxane, 1 mL) was stirred 1h at r.t., then neutralized with CH₂Cl₂/MeOH/NH₄OH 90:10:0.25 andevaporated. Chromatography of the residue (SiO₂, CH₂Cl₂/MeOH/NH₄OH90:10:0.25) afforded the title compound (32 mg, 74%). Off-white foam, MS(ISP) 359.6 (M+).

Example 2(RS,RS,RS)-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-thiazolidin-3-yl-methanone

[0155]

[0156] a)(RS,RS,RS)-[9,10-Dimethoxy-3-(thiazolidine-3-carbonyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0157] The title compound was produced in accordance with the generalmethod of Example 1d from(RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (Example 1 c) and thiazolidine.Off-white solid, MS (ISP) 478.3 (M+H)⁺.

[0158] b)(RS,RS,RS)-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-thiazolidin-3-yl-methanone

[0159] The title compound was produced in accordance with the generalmethod of Example 1 e from(RS,RS,RS)-[9,10-dimethoxy-3-(thiazolidine-3-carbonyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. White foam, MS (ISP) 378.3 (M+H)⁺.

Example 3(RS,RS,RS)-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azetidin-1-yl-methanone

[0160]

[0161] a)(RS,RS,RS)-[3-(Azetidine-1-carbonyl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0162] The title compound was produced in accordance with the generalmethod of Example 1 d from(RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (Example 1c) and azetidine. Lightyellow solid, MS (ISP) 446.3 (M+H)⁺.

[0163] b)(RS,RS,RS)-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azetidin-1-yl-methanone.

[0164] The title compound was produced in accordance with the generalmethod of Example 1e from(RS,RS,RS)-[3-(azetidine-1-carbonyl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. White foam, MS (ISP) 346.2 (M+H)⁺.

Example 4(SS)-1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carbonyl)-pyrrolidine-2-carbonitrile

[0165]

[0166] a)[(RS,RS,RS)-3-((SS)-2-Cyano-pyrrolidine-1-carbonyl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0167] The title compound was prepared in accordance with the generalmethod of Example 1d from(RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (Example 1c) and (S)-2-cyano-pyrrolidine (EP1258476). Yellow solid,MS (ISP) 485.5 (M+H)⁺.

[0168] b)(S)-1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carbonyl)-pyrrolidine-2-carbonitrile

[0169] The title compound was prepared in accordance with the generalmethod of Example 1 e from[(RS,RS,RS)-3-((SS)-2-cyano-pyrrolidine-1-carbonyl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Light yellow solid, MS (ISP) 385.2 (M+H)⁺.

Example 51-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one

[0170]

[0171] a)(RS,RS,RS)-(2-tert-Butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-carbamic Acid 2-trimethylsilanyl-ethyl Ester

[0172] A mixture of(RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (Example 1c, 6.91 g, 17.0 mmol), diphenylphosphoryl azide (7.40 g,25.6 mmol), triethylamine (1.72 g, 17.0 mmol),2-(trimethylsilyl)-ethanol (30.2 g, 256 mmol) and toluene (40 mL) washeated 48 h at 80° C. under a gentle nitrogen stream. The reactionmixture was then concentrated in vacuo, the residue chromatographed(SiO₂, CH₂Cl₂/MeOH/NH₄OH 80:1:0.2), and the product fractions trituratedin hexane/ethyl acetate 1:1 to afford the title compound (5.22 g, 59%).White solid, MS (ISP) 522.4 (M+H)⁺.

[0173] b)(RS,RS,RS)-(3-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic Acid Tert-Butyl Ester

[0174] A suspension of(RS,RS,RS)-(2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-carbamicacid 2-trimethylsilanyl-ethyl ester (5.22 g, 10.0 mmol) intetrabutylammonium fluoride solution (1 M in THF, 42 mL, 42 mmol) washeated 90 min at 50° C. The resultant solution was concentrated in vacuoand chromatographed (CH₂Cl₂/MeOH/NH₄OH 95:5:0.25) to afford the titlecompound (3.59 g, 95%). Light yellow solid, MS (ISP) 378.4 (M+H)⁺;t_(R)=7.2 and 18.9 min (Chiralpak® AD 25×0.03 cm,heptane/ethanol/triethylamine 70:30:0.3, flow rate 4 μL/min).

[0175] c)(RS,RS,RS)-[3-(5-Chloro-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0176] 5-Chlorovaleryl chloride (466 mg, 2.91 mmol) was added at a 0° C.to a solution of(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (1.00 g, 2.65 mmol) and triethylamine (295 mg,2.91 mmol), and the resultant suspension was allowed to reach r.t. over30 min. The reaction mixture was then partitioned betweendichloromethane and water, the organic layer was washed with brine,dried (MgSO₄), and evaporated. Chromatrography of the residue (SiO₂,CH₂Cl₂/MeOH/NH₄OH 80:2:0.2) afforded the title compound (1.23 g, 94%).White solid, MS (ISP) 496.3 (M+H)⁺.

[0177] d)(RS,RS,RS)-[9,10-Dimethoxy-3-(2-oxo-piperidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0178] A solution of(RS,RS,RS)-[3-(5-chloro-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (1.22 g, 2.46mmol) in N,N-dimethylformamide (18 mL) was treated with sodium iodide(369 mg, 2.46 mmol) and sodium hydride (60% dispersion in oil, 197 mg,4.92 mmol) and stirred 2 h at r.t., then poured onto ice and partitionedbetween heptane/ethyl acetate 1:1 and water. The organic layer waswashed with brine, dried (MgSO₄), and evaporated. Chromatrography of theresidue (SiO₂, CH₂Cl₂/MeOH/NH₄OH 80:2:0.2) afforded the title compound(769 mg, 68%). White solid, MS (ISP) 460.3 (M+H)⁺.

[0179] e)1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one

[0180] The title compound was prepared in accordance with the generalmethod of Example 1e from(RS,RS,RS)-[9,10-dimethoxy-3-(2-oxo-piperidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. White solid, MS (ISP) 360.3 (M+H)⁺.

Examples 6 and 7(−)—(S,S,S)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one

[0181]

[0182] and

(+)—(R,R,R)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one

[0183]

[0184](RS,RS,RS)-[9,10-Dimethoxy-3-(2-oxo-piperidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester (580 mg, 1.61 mmol) was dissolved inethanol/heptane 3:2 (5 mL) and subjected to preparative HPLC (Chiralpak®AD column, heptane/ethanol 80:20).

[0185](−)-(S,S,S)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one:Light yellow semisolid, 220 mg (38%), t_(R)=32.0 min (Chiralpak® AD25×0.46 cm, heptane/ethanol 80:20, flow rate 1 mL/min).(+)-(R,R,R)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one: Light yellow semisolid, 207 mg(36%), t_(R)=55.4 min (Chiralpak® AD 25×0.46 cm, heptane/ethanol 80:20,flow rate 1 mL/min).

Example 81-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-piperidin-2-one

[0186]

[0187] a)(RS,RS,RS)-[3-(5-Chloro-3-methyl-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0188] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 5-chloro-3-methylvaleryl chloride(DE2621576). White solid, MS (ISP) 510.4 (M+H)⁺.

[0189] b)(RS,RS,RS)-[9,10-Dimethoxy-3-(4-methyl-2-oxo-piperidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0190] The title compound was produced in accordance with the generalmethod of Example 5d from(RS,RS,RS)-[3-(5-chloro-3-methyl-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Light yellowsolid, MS (ISP) 474.3 (M+H)⁺.

[0191] c)1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-piperidin-2-one

[0192] The title compound was produced in accordance with the generalmethod of Example 1e from(RS,RS,RS)-[9,10-dimethoxy-3-(4-methyl-2-oxo-piperidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. White solid, MS (ISP) 374.2 (M+H)⁺.

Example 9(RS,RS,RS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-pyrrolidin-2-one

[0193]

[0194] a)(RS,RS,RS)-[3-(4-Chloro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0195] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 4-chlorobutyryl chloride. Whitesolid, MS (ISP) 482.4 (M+H)⁺.

[0196] b)(RS,RS,RS)-[9,10-Dimethoxy-3-(2-oxo-pyrrolidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0197] The title compound was produced in accordance with the generalmethod of Example 5d from(RS,RS,RS)-[3-(4-chloro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Light yellow solid, MS (ISP) 446.3 (M+H)⁺.

[0198] c)(RS,RS,RS)-[3-(4-Chloro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0199] The title compound was produced in accordance with the generalmethod of Example 1 e from(RS,RS,RS)-[9,10-dimethoxy-3-(2-oxo-pyrrolidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. White solid, MS(ISP) 346.2 (M+H)⁺.

Example 101-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one

[0200]

[0201] a)[(RS,RS,RS)-3-(4-Chloro-3-methyl-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0202] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and4-chloro-3-methylbutyryl chloride (Chem. Ber. 1964, 97, 2544). Whitesolid, MS (ISP) 496.3 (M+H)⁺.

[0203] b)[(RS,RS,RS)-9,10-Dimethoxy-3-(4-methyl-2-oxo-pyrrolidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0204] The title compound was produced in accordance with the generalmethod of Example 5d from[(RS,RS,RS)-3-(4-chloro-3-methyl-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Light yellow solid, MS (ISP) 460.3 (M+H)⁺.

[0205] c)1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one

[0206] The title compound was produced in accordance with the generalmethod of Example 1 e from[(RS,RS,RS)-9,10-dimethoxy-3-(4-methyl-2-oxo-pyrrolidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Light yellow solid, MS (ISP) 360.3 (M+H)⁺.

Example 111-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-ethyl-pyrrolidin-2-one

[0207]

[0208] a)(RS,RS,RS)-[3-(3-Chloromethyl-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0209] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 3-(chloromethyl)-valeryl chloride(J. Korean Chem. Soc. 1991, 35, 756). White solid, MS (ISP) 510.4(M+H)⁺.

[0210] b)(RS,RS,RS)-[3-(4-Ethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0211] The title compound was produced in accordance with the generalmethod of Example 5d from(RS,RS,RS)-[3-(3-chloromethyl-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Light yellowsolid, MS (ISP) 474.2 (M+H)⁺.

[0212] c)1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-ethyl-pyrrolidin-2-one

[0213] The title compound was produced in accordance with the generalmethod of Example 1e from(RS,RS,RS)-[3-(4-ethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Light yellow solid, MS (ISP) 374.5 (M+H)⁺.

Example 12(RS,RS,RS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5,6-dihydro-1H-pyridin-2-one

[0214]

[0215] a)(RS,RS,RS)-(3-But-3-enylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicAcid Tert-Butyl Ester

[0216] 4-Bromo-2-butene (60 mg, 0.45 mmol) and triethylamine (49 mg,0.49 mmol) were added to a solution of(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b; 153mg, 0.41 mmol), and the mixture was heated at reflux, then after 18 hanother portion of 4-bromo-2-butene (60 mg, 0.45 mmol) and triethylamine(49 mg, 0.49 mmol) was added. After another 24 h at reflux, the reactionmixture was poured onto ice and partitioned between 1 M aq. sodiumhydroxide solution and ethyl acetate. The organic layer was washed withbrine, dried (MgSO₄), and evaporated. Chromatography (SiO₂,CH₂Cl₂/MeOH/NH₄OH 95:5:0.25) afforded the title compound (77 mg, 44%).Off-white solid, MS (ISP) 432.4 (M+H)⁺.

[0217] b)(RS,RS,RS)-[3-(Acryloyl-but-3-enyl-amino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0218] Acryloyl chloride (18 mg, 0.20 mmol) was added dropwise at 0° C.to a solution of(RS,RS,RS)-(3-but-3-enylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (77 mg, 0.18 mmol) and triethylamine (20 mg, 0.20mmol) in dichloromethane (1.5 mL). After 30 min at 0° C. the reactionmixture was partitioned between 2 M aq. sodium carbonate solution andethyl acetate. The organic layer was washed with brine, dried (MgSO₄),and evaporated. Chromatography (SiO₂, CH₂Cl₂/MeOH/NH₄OH 95:5:0.25)afforded the title compound (65 mg, 75%). White solid, MS (ISP) 486.5(M+H)⁺.

[0219] c)(RS,RS,RS)-[9,10-Dimethoxy-3-(6-oxo-3,6-dihydro-2H-pyridin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0220] Tetraisopropyl orthotitanate (7.6 mg, 27 μmol) andBis(tricyclohexylphosphine)-benzylideneruthenium(IV)dichloride (11 mg,13 μmol) were added to a solution of(RS,RS,RS)-[3-(acryloyl-but-3-enyl-amino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester (65 mg, 0.13 mmol) in dichloromethane (2.5 mL).The reaction mixture was stirred 45 min at r.t., then partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried (MgSO₄), and evaporated. Chromatography (SiO₂,CH₂Cl₂/MeOH/NH₄OH 95:5:0.25) afforded the title compound (59 mg, 96%).White solid, MS (ISP) 458.4 (M+H)⁺.

[0221] d)(RS,RS,RS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5,6-dihydro-1H-pyridin-2-one

[0222] The title compound was produced in accordance with the generalmethod of Example 1 e from(RS,RS,RS)-[9,10-dimethoxy-3-(6-oxo-3,6-dihydro-2H-pyridin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. White foam, MS (ISP) 358.2 (M+H)⁺.

Example 131-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azepan-2-one

[0223]

[0224] a)(RS,RS,RS)-2-Benzylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid Ethyl Ester

[0225] Trifluoroacetic acid (20 mL) was added at 0° C. to a solution of2-amino-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylicacid ethyl ester (Example 1a; 2.00 g, 6.02 mmol) in tetrahydrofuran (20mL), then after 30 min the homogeneous solution was treated with sodiumborohydride (474 mg, 12.0 mmol) and stirred for another 40 min. Thereaction mixture was concentrated in vacuo and the residue partitionedbetween 2 M aq. sodium hydroxide solution and dichloromethane. Theorganic layer was washed with brine, dried (MgSO₄) and evaporated. Theresidue was dissolved in methanol (37 mL) and acetic acid (9 mL) andtreated with benzaldehyde (723 mg, 6.81 mmol), then sodiumcyanoborohydride (526 mg, 7.95 mmol) was added portionwise at r.t. over1 h. The reaction mixture was stirred another 15 min, then partitionedbetween sat. aq. sodium hydrogencarbonate solution and dichoromethane.The organic layer was washed with brine, dried (MgSO₄), and evaporated.Chromatrography of the residue (SiO₂, CH₂Cl₂/EtOAc 4:1, after elution ofdibenzylated side-product, CH₂Cl₂/MeOH/NH₄OH 95:5:0.25) afforded thetitle compound (1.31 g, 51%). Red oil, MS (ISP) 425.2 (M+H)⁺.

[0226] b)(RS,RS,RS)-2-(Benzyl-tert-butoxycarbonyl-amino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic Acid Ethyl Ester

[0227] Di-tert-butyl-dicarbonate (752 mg, 3.38 mmol) was added at r.t.to solution of(RS,RS,RS)-2-benzylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid ethyl ester (1.30 g, 3.07 mmol) in dichloromethane (13 mL). After16 h the solution was evaporated and the residue chromatographed (SiO₂,heptane-EtOAc gradient) to produce the title compound (1.24 g, 77%).Yellow foam, MS (ISP) 525.3 (M+H)⁺.

[0228] c)(RS,RS,RS)-[2-(Benzyl-tert-butoxycarbonyl-amino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl]-carbamic Acid Benzyl Ester

[0229] Potassium hydroxide pellets (86%, 1.53 g, 23.4 mmol) were addedto a solution of(RS,RS,RS)-2-(benzyl-tert-butoxycarbonyl-amino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid ethyl ester (1.20 g, 2.28 mmol) in water/tetrahydrofuran 1:1 (24mL), and the mixture was heated at reflux for 72 h. After cooling, thesolution was neutralized with 1 M aq. potassium phosphate buffer (pH6.85) and extracted three times with dichloromethane. The organic layerswere pooled, dried (MgSO₄), and evaporated. The residue was suspended intoluene (24 mL) and treated with triethylamine (230 mg, 2.28 mmol) anddiphenylphosphoryl azide (659 mg, 2.28 mmol). The reaction was kept atr.t. for 90 min and heated at 80° C. for 90 min, then benzyl alcohol(369 mg, 3.41 mmol) was added, and the reaction temperature was kept at100° C. for 18 h. The reaction mixture was diluted with dichloromethaneand washed with 10% aq. citric acid solution, 1 M aq. sodium hydroxidesolution, and brine, dried (MgSO₄), and evaporated. Chromatography(SiO₂, heptane/EtOAc gradient) afforded the title compound (805 mg,59%). Light yellow foam, MS (ISP) 602.3 (M+H)⁺.

[0230] d)(RS,RS,RS)-(3-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-benzyl-carbamicAcid Tert-Butyl Ester

[0231] A solution of(RS,RS,RS)-[2-(benzyl-tert-butoxycarbonyl-amino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl]-carbamicacid benzyl ester (802 mg, 1.33 mmol) in acetic acid (24 mL) washydrogenated (1 bar, r.t., 3 h) in the presence of palladium (10% onactivated charcoal, 40 mg), then the catalyst was removed by filtrationand the filtrate evaporated. Chromatography (SiO₂, CH₂Cl₂/MeOH/NH₄OH90:10:0.25) afforded the title compound (402 mg, 65%). Light yellowfoam, MS (ISP) 468.4 (M+H)⁺.

[0232] e)(RS,RS,RS)-Benzyl-[3-(6-chloro-hexanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0233] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-benzyl-carbamicacid tert-butyl ester and 6-chlorohexanoyl chloride. Yellow oil, MS(ISP) 600.4 (M+H)⁺.

[0234] f)(RS,RS,RS)-Benzyl-[9,10-dimethoxy-3-(2-oxo-azepan-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0235] The title compound was produced in accordance with the generalmethod of Example 5d from(RS,RS,RS)-benzyl-[3-(6-chloro-hexanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Off-whitesolid, MS (ISP) 564.4 (M+H)⁺.

[0236] g)(RS,RS,RS)-1-(2-Benzylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azepan-2-one

[0237] The title compound was produced in accordance with the generalmethod of Example 1e from(RS,RS,RS)-benzyl-[9,10-dimethoxy-3-(2-oxo-azepan-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Light yellowsolid, MS (ISP) 464.5 (M+H)⁺.

[0238] h)1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azepan-2-one

[0239] A solution of(RS,RS,RS)-1-(2-benzylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azepan-2-one(35 mg, 75 μmol) was hydrogenated (3 bar, r.t., 3 h) in the presence ofpalladium (10% on activated charcoal), then the catalyst was removed byfiltration and the filtrate evaporated. Chromatography (SiO₂,CH₂Cl₂/MeOH/NH₄OH 95:5:0.25) afforded the title compound (10 mg, 43%).Light yellow solid, MS (ISP) 374.2 (M+H)⁺.

Example 14(RS,RS,RS)-3-(1,1-Dioxo-1,2-thiazolidin-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine

[0240]

[0241] a)(RS,RS,RS)-[3-(3-Chloro-propane-1-sulfonylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0242] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 3-chloropropanesulfonyl chloride.White solid, MS (ISP) 516.3 (M−H)⁻.

[0243] b)(RS,RS,RS)-[3-(1,1-Dioxoisothiazolidin-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0244] The title compound was produced in accordance with the generalmethod of Example 5d from(RS,RS,RS)-[3-(3-chloro-propane-1-sulfonylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Off-white solid, MS (ISP) 482.3 (M+H)⁺.

[0245] c)(RS,RS,RS)-3-(1,1-Dioxo-1,2-thiazolidin-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine

[0246] The title compound was produced in accordance with the generalmethod of Example 1e from(RS,RS,RS)-[3-(1,1-dioxoisothiazolidin-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. White foam, MS(ISP) 382.3 (M+H)⁺.

Example 15(RS,RS,RS)-3-(1,1-Dioxo[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine

[0247]

[0248] a)(RS,RS,RS)-[3-(4-Chloro-butane-1-sulfonylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0249] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 4-chlorobutanesulfonyl chloride(DE1300933). White solid, MS (ISP) 532.3 (M+H)⁺.

[0250] b)(RS,RS,RS)-[3-(1,1-Dioxo[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0251] The title compound was produced in accordance with the generalmethod of Example 5d from(RS,RS,RS)-[3-(4-chloro-butane-1-sulfonylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. White solid, MS(ISP) 496.3 (M+H)⁺.

[0252] c) (RS,RS,RS)-3-(1,1-Dioxo[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine

[0253] The title compound was produced in accordance with the generalmethod of Example 1e from(RS,RS,RS)-[3-(1,1-dioxo[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. White solid, MS (ISP) 396.3 (M+H)⁺.

Example 16(S,S,S)-3-(1,1-Dioxo-[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine

[0254]

[0255] a) (S)—(6,7-Dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic Acid EthylEster

[0256] The title compound was produced in >99.5% e.e. from(6,7-Dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid ethylester (Synthesis 1987, 474) by fractional crystallization with(−)-2′-nitrotartranilic acid, in accordance with the general procedureof Montzka et al. (U.S. Pat. No. 3,452,086). Light yellow solid, MS(ISP) 280.2 (M+H)⁺, t_(R)=6.4 min (Chiralcel® ODH 15×0.21 cm,heptane/2-propanol/triethylamine 75:25:0.15, flow rate 150 μL/min).

[0257] b)(S,S,S)-(3-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicAcid Tert-Butyl Ester

[0258] The title compound was produced from(S)-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acidethyl ester, in accordance with the synthesis of the racemate,(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamictert-butyl ester (Example 5b). Off-white solid, t_(R)=19.3 min(Chiralpak® AD 25×0.03 cm, heptane/ethanol/triethylamine 70:30:0.3, flowrate 4 μL/min).

[0259] c)(S,S,S)-3-(11,1-Dioxo-[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine

[0260] The title compound was produced in accordance with the synthesisof the racemate,(RS,RS,RS)-3-(1,1-dioxo[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine(Example 15). Off-white foam.

Examples 17 and 18(SR)-1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one

[0261]

[0262] and

(RS,RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one

[0263]

[0264] The title compounds were produced from1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one(Example 10) by chromatographic separation (SiO₂, CH₂Cl₂/MeOH/NH₄OH90:10:0.25).(SR)-1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one:Light yellow foam, R_(f)=0.20.

[0265](RS,RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one: Light yellow solid,R_(f)=0.15.

Examples 19 and 20(R)-1-((S,S,S)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one

[0266]

[0267] and

(S)—1-((R,R,R)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one

[0268]

[0269] The title compounds were produced in accordance with the generalmethod of Examples 6 and 7 from(SR)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one(Example 17).(R)-1-((S,S,S)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one:Off-white foam, t_(R)=40.1 min (Chiralpak® AD 25×0.46 cm,heptane/ethanol 80:20, flow rate 1 mL/min).(S)-1-((R,R,R)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one:Off-white foam, t_(R)=66.0 min (Chiralpak® AD 25×0.46 cm,heptane/ethanol 80:20, flow rate 1 mL/min).

Examples 21 and 22(S,S,S,S)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one

[0270]

[0271] and

(R,R,R,R)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one

[0272]

[0273] The title compounds were produced in accordance with the generalmethod of Examples 6 and 7 from(RS,RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one (Example 18).(S,S,S,S)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one: Off-white foam,t_(R)=29.4 min (Chiralpak® AD 25×0.46 cm, heptane/ethanol 80:20, flowrate 1 mL/min).(R,R,R,R)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one:Off-white foam, t_(R)=41.8 min (Chiralpak® AD 25×0.46 cm,heptane/ethanol 80:20, flow rate 1 mL/min).

Example 231-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

[0274]

[0275] a) 4-Fluoromethyl-dihydro-furan-2-one

[0276] A solution of 4-hydroxymethyl-dihydro-furan-2-one (Tetrahedron1994, 50, 6839; 1.02 g, 8.78 mmol) and bis(2-methoxyethyl)aminosulfurtrifluoride (3.88 g, 17.6 mmol) in chloroform (4.4 mL) was stirred at40° C. for 1 h, then poured onto ice and partitioned between sat. aq.sodium hydrogencarbonate solution and dichloromethane. The organic layerwas washed with brine, dried (MgSO₄), and evaporated. Chromatography(SiO₂, heptane-ethyl acetate gradient) afforded the title compound (576mg, 56%). Colourless liquid, MS (EI) 118.9 (M+H)⁺.

[0277] b) 3-Chloromethyl-4-fluoro-butyryl Chloride

[0278] A mixture of 4-fluoromethyl-dihydro-furan-2-one (871 mg, 7.37mmol), thionyl chloride (4.39 g, 36.9 mmol), and zinc chloride (60 mg,0.44 mmol) was stirred 72 h at 80° C., then excess thionyl chloride wasremoved by distillation. Kugelrohr distillation of the residue (85° C.,0.2 mbar) afforded the title compound (450 mg, 35%). Colourless liquid,¹H-NMR (300 MHz, CDCl₃): 4.65-4.55 (m, 1H), 4.50-4.40 (m, 1H), 3.70-3.60(m, 2H), 3.25-3.05 (m, 2H), 2.80-2.60 (m, 1H).

[0279] c)(RS,RS,RS)-[3-(3-Chloromethyl-4-fluoro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0280] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 3-chloromethyl-4-fluoro-butyrylchloride. White solid, MS (ISP) 514.5 (M+H)⁺.

[0281] d)(RS,RS,RS)-[3-(4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0282] The title compound was produced in accordance with the generalmethod of Example 5d from(RS,RS,RS)-[3-(3-chloromethyl-4-fluoro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Off-white foam, MS (ISP) 478.5 (M+H)⁺.

[0283] e)1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

[0284] The title compound was produced in accordance with the generalmethod of Example 1 e from(RS,RS,RS)-[3-(4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Light yellow oil, MS (ISP) 378.5 (M+H)⁺.

Example 241-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-piperidin-2-one

[0285]

[0286] a) 5-Chloro-4-methyl-pentanoyl Chloride

[0287] The title compound was produced in accordance with the generalmethod of Example 23b from 5-methyl-tetrahydro-pyran-2-one (Tetrahedron1995, 51, 6237). Colourless liquid, ¹H-NMR (300 MHz, CDCl₃): 3.50-3.40(m, 2H), 2.95 (td, 2H), 2.00-1.85 (m, 2H), 1.70-1.60 (m, 1H), 1.04 (d,3H).

[0288] b)(RS,RS,RS)-[3-(5-Chloro-4-methyl-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0289] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 5-chloro-4-methyl-pentanoylchloride. Off-white solid, MS (ISP) 510.6 (M+H)⁺.

[0290] c)(RS,RS,RS)-[9,10-Dimethoxy-3-(5-methyl-2-oxo-piperidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0291] The title compound was produced in accordance with the generalmethod of Example 5d from(RS,RS,RS)-[3-(5-chloro-4-methyl-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Light yellowoil, MS (ISP) 474.5 (M+H)⁺.

[0292] d)1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-piperidin-2-one

[0293] The title compound was produced in accordance with the generalmethod of Example 1 e from(RS,RS,RS)-[9,10-dimethoxy-3-(5-methyl-2-oxo-piperidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Light yellowsolid, MS (ISP) 374.5 (M+H)⁺.

Example 25(RS,RS,RS)—N-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-propionamide

[0294]

[0295] a)(RS,RS,RS)-(9,10-Dimethoxy-3-propionylamino-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic Acid Tert-Butyl Ester

[0296] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) andpropionyl chloride. Light yellow solid, MS (ISP) 434.6 (M+H)⁺.

[0297] b)(RS,RS,RS)—N-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-propionamide

[0298] The title compound was produced in accordance with the generalmethod of Example 1e from(RS,RS,RS)-(9,10-dimethoxy-3-propionylamino-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester. Off-whitesolid, MS (ISP) 334.5 (M+H)⁺.

Example 26(RS,RS,RS)—N-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-butyramide

[0299]

[0300] The title compound was produced in accordance with the generalmethods of Example 5c and 1e from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and butyryl chloride. Yellow solid,MS (ISP) 348.5 (M+H)⁺.

Example 27 Cyclopropanecarboxylic acid((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-amide

[0301]

[0302] The title compound was produced in accordance with the generalmethods of Example 5c and le from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and cyclopropanecarbonyl chloride.Off-white solid, MS (ISP) 346.3 (M+H)⁺.

Examples 28 and 29(SR)-1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

[0303]

[0304] and

(RS,RS,RS,RS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

[0305]

[0306] The title compounds were produced from1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one(Example 23) by chromatographic separation (SiO₂, CH₂Cl₂/MeOH/NH₄OH80:1:0.2, then 95:5:0.25).

[0307](SR)-1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one:Yellow oil, R_(f)=0.45 (CH₂Cl₂/MeOH/NH₄OH 90:10:0.25).

[0308](RS,RS,RS,RS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one: Light yellowsolid, R_(f) 0.40 (CH₂Cl₂/MeOH/NH₄OH 90:10:0.25).

Example 30(S)-1-((S,S,S)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one Dihydrochloride

[0309]

[0310] a)[(S,S,S)-3-(3-Chloromethyl-4-fluoro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0311] The title compound was produced in accordance with the generalmethod of Example 5c from(S,S,S)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 16b) and 3-chloromethyl-4-fluoro-butyrylchloride (Example 23b). Off-white solid.

[0312] b)[(S,S,S)-3-((S)-4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester and[(S,S,S)-3-((R)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0313] Sodium hydride (55-65% dispersion in oil, 1.14 g, 28.5 mmol) wasadded to a suspension of[(S,S,S)-3-(3-chloromethyl-4-fluoro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester (6.72 g, 13.1 mmol) in N,N-dimethylformamide (95mL) at r.t., then after 1 h the reaction mixture was poured onto ice andpartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (MgSO₄), and evaporated. Chromatography (SiO₂,cyclohexane/2-propanol 4:1) afforded[(S,S,S)-3-((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester (2.40 g, 38%) and the epimer,[(S,S,S)-3-((R)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (2.73 g, 44%).

[0314][(S,S,S)-3-((S)-4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester: Light yellowfoam, R_(f)=0.6 (SiO₂, cyclohexane/2-propanol 1:1).

[0315][(S,S,S)-3-((R)-4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester: Light yellow foam, R_(f)=0.4 (SiO₂,cyclohexane/2-propanol 1:1).

[0316] c)(S)-1-((S,S,S)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-oneDihydrochloride

[0317][(S,S,S)-3-((S)-4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (2.40 g, 5.02mmol) was converted to(S)-1-((S,S,S)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one in accordancewith the general method of Example 1e. The product was dissolved in2-propanol (10 mL) and treated with hydrogen chloride (5-6 M in2-propanol, 37 mL). The suspension formed was stirred for 64 h at r.t.,then the precipitate was collected by filtration and dried, to affordthe title compound (2.04 g, 91%). White solid, m.p. >300° C.

Example 31(R)-1-((S,S,S)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one Dihydrochloride

[0318]

[0319] The title compound was produced in accordance with the generalmethod of Example 30c from[(S,S,S)-3-((R)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (Example 30b).White solid, m.p. >300° C.

Example 323-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-oxazolidin-2-one

[0320]

[0321] The title compound was produced in accordance with the generalmethods of Example 5c, 5d, and 1e from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 2-chloroethyl chloroformate.Light yellow solid, MS (ISP) 348.5 (M+H)⁺.

Example 333-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-[1,3]oxazinan-2-one

[0322]

[0323] a)((RS,RS,RS)-2-tert-Butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-carbamicacid 3-chloro-propyl Ester

[0324] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 3-chloropropyl chloroformate.Off-white solid, MS (ISP) 498.4 (M+H)⁺.

[0325] b)[(RS,RS,RS)-9,10-Dimethoxy-3-(2-oxo-[1,3]oxazinan-3-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0326] The title compound was produced in accordance with the generalmethod of Example 5d from((RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-carbamicacid 3-chloro-propyl ester. Off-white solid, MS (ISP) 462.4 (M+H)⁺.

[0327] c)3-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-[1,3]oxazinan-2-one

[0328] The title compound was produced in accordance with the generalmethod of Example 1 e from[(RS,RS,RS)-9,10-dimethoxy-3-(2-oxo-[1,3]oxazinan-3-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Yellow solid, MS (ISP) 362.5 (M+H)⁺.

Example 341-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-pyrrolidin-2-one

[0329]

[0330] a) 4-Chloro-Pentanoyl Chloride

[0331] The title compound was produced in accordance with the generalmethod of Example 23b from γ-valerolactone. Colourless liquid, ¹H-NMR(300 MHz, CDCl₃): 4.10-4.00 (m, 1H), 3.25-3.05 (m, 2H), 2.25-2.15 (m,1H), 2.05-1.95 (m, 1H), 1.55 (d, 3H).

[0332] b)[(RS,RS,RS)-3-(4-Chloro-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0333] The title compound was produced in accordance with the generalmethod of Example 5c from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b) and 4-chloro-pentanoyl chloride.Off-white solid, MS (ISP) 496.4 (M+H)⁺.

[0334] c)1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-pyrrolidin-2-one

[0335] The title compound was produced in accordance with the generalmethods of Example 5d and le from[(RS,RS,RS)-3-(4-chloro-pentanoylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Yellow solid, MS (ISP) 360.1 (M+H)⁺.

Example 353-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-fluoromethyl-oxazolidin-2-one

[0336]

[0337] a)[(RS,RS,RS)-3-(2-Chloro-1-fluoromethyl-ethoxycarbonylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0338] Pyridine (69 mg, 0.87 mmol) was added dropwise at 0° C. to asolution of 1-chloro-3-fluoroisopropanol (34 mg, 0.29 mmol) indichloromethane (0.8 mL), then the solution was allowed to reach r.t.over 2 h. After cooling again to 0° C.,(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamicacid tert-butyl ester (Example 5b, 100 mg, 0.26 mmol), pyridine (23 mg,0.29 mmol), and 4-dimethylaminopyridine (1 mg, 8 μmol) were added. Thereaction mixture was allowed to reach r.t. over 16 h, then partitionedbetween sat. aq. ammonium chloride solution and ether. The organic layerwas washed with water, dried (MgSO₄), and evaporated. Chromatography(SiO₂, heptane-ethyl acetate gradient) produced the title compound (65mg, 48%). White solid, MS (ISP) 516.5 (M+H)⁺.

[0339] b)[(RS,RS,RS)-3-(5-Fluoromethyl-2-oxo-oxazolidin-3-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic Acid Tert-Butyl Ester

[0340] The title compound was produced in accordance with the generalmethod of Example 5d from[(RS,RS,RS)-3-(2-chloro-1-fluoromethyl-ethoxycarbonylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. White solid, MS(ISP) 480.5 (M+H)⁺.

[0341] c)3-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-fluoromethyl-oxazolidin-2-one

[0342] The title compound was produced in accordance with the generalmethod of Example 1 e from[(RS,RS,RS)-3-(5-fluoromethyl-2-oxo-oxazolidin-3-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester. Yellow solid,MS (ISP) 380.4 (M+H)⁺.

Example 361-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-3-methyl-pyrrolidin-2-one

[0343]

[0344] a) 4-Chloro-2-methyl-butyryl Chloride

[0345] The title compound was produced in accordance with the generalmethod of Example 23b from γ-valerolactone. Colourless liquid, ¹H-NMR(300 MHz, CDCl₃): 3.61 (t, 2H), 3.25-3.15 (m, 1H), 2.40-2.25 (m, 1H),2.00-1.85 (m, 1H), 1.36 (d, 3H).

[0346] b)[(RS,RS,RS)-3-(4-Chloro-2-methyl-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0347] The title compound was produced in accordance with the generalmethod of Example 5c from (RS,RS,RS)—(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and4-chloro-2-methyl-butyryl chloride. Off-white solid, MS (ISP) 496.4(M+H)⁺.

[0348] c)1-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-3-methyl-pyrrolidin-2-one

[0349] The title compound was produced in accordance with the generalmethod of Example 5d and 1e from[(RS,RS,RS)-3-(4-chloro-2-methyl-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Yellow solid, MS (ISP) 360.5 (M+H)⁺.

Example 373-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-oxazolidin-2-one

[0350]

[0351] a)((RS,RS,RS)-2-tert-Butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-carbamicacid 2-chloro-1-methyl-ethyl Ester

[0352] The title compound was produced in accordance with the generalmethod of Example 35a from(RS,RS,RS)-(3-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl)-carbamic acid tert-butyl ester (Example 5b) and1-chloro-propan-2-ol (J. Chem. Soc. Perkin Trans. 1 1983, 3019).Off-white solid, MS (ISP) 498.4 (M+H)⁺.

[0353] b)[(RS,RS,RS)-9,10-Dimethoxy-3-(5-methyl-2-oxo-oxazolidin-3-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicAcid Tert-Butyl Ester

[0354] The title compound was produced in accordance with the generalmethod of Example 5d from((RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-carbamicacid 2-chloro-1-methyl-ethyl ester. White solid, MS (ISP) 462.4 (M+H)⁺.

[0355] c)3-((RS,RS,RS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-oxazolidin-2-one

[0356] The title compound was produced in accordance with the generalmethod of Example 1e from[(RS,RS,RS)-9,10-dimethoxy-3-(5-methyl-2-oxo-oxazolidin-3-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamicacid tert-butyl ester. Light yellow solid, MS (ISP) 362.4 (M+H)⁺.

Galenical Examples Example A

[0357] Film coated tablets containing the following ingredients can bemanufactured in a conventional manner: Ingredients Per tablet Kernel:Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mgSodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg(Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methylcellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg

[0358] The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magnesium stearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aq.solution/suspension of the above mentioned film coat.

Example B

[0359] Capsules containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per capsule Compound of formula(I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg

[0360] The components are sieved and mixed and filled into capsules ofsize 2.

Example C

[0361] Injection solutions can have the following composition:Ingredients Compound of formula (I) 3.0 mg Polyethylene Glycol 400 150.0mg Acetic Acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

[0362] The active ingredient is dissolved in a mixture of polyethyleneglycol 400 and water for injection (part). The pH is adjusted to 5.0 byacetic acid. The volume is adjusted to 1.0 ml by addition of theresidual amount of water. The solution is filtered, filled into vialsusing an appropriate overage and sterilized.

Example D

[0363] Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner: Ingredients Capsule contentsCompound of formula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated Soya beanoil 8.0 mg Partially hydrogenated plant oils 34.0 mg Soya bean oil 110.0mg Weight of capsule contents 165.0 mg Gelatin capsule Gelatin 75.0 mgGlycerol 85% 32.0 mg Karion 83 8.0 mg (dry matter) Titan dioxide 0.4 mgIron oxide yellow 1.1 mg

[0364] The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

[0365] Sachets containing the following ingredients can be manufacturedin a conventional manner: Ingredients Compound of formula (I) 50.0 mgLactose, fine powder 1015.0 mg Microcristalline cellulose (AVICEL PH102) 1400.0 mg Sodium carboxymethyl cellulose 14.0 mgPolyvinylpyrrolidon K 30 10.0 mg Magnesium stearate 10.0 mg Flavoringadditives 1.0 mg

[0366] The active ingredient is mixed with lactose, microcrystallinecellulose and sodium carboxymethyl cellulose and granulated with amixture of polyvinylpyrrolidone in water. The granulate is mixed withmagnesium stearate and the flavouring additives and filled into sachets.

What is claimed is:
 1. A compound of formula (I)

wherein R¹ is —C(O)—N(R¹)R⁶ or —N(R⁵)R¹; R², R³ and R⁴ are eachindependently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy,lower alkenyl, substituted lower alkyl, substituted lower alkoxy, orsubstituted lower alkenyl, wherein substituted lower alkyl, substitutedlower alkoxy and substituted lower alkenyl are lower alkyl, lower alkoxyand lower alkenyl, respectively, which are independently substituted bya group selected from the group consisting of lower alkoxycarbonyl, aryland heterocyclyl; R⁵ is hydrogen, lower alkyl, halogenated lower alkylor cycloalkyl; R⁶ is lower alkylsulfonyl, halogenated loweralkylsulfonyl, cycloalkylsulfonyl, lower alkylcarbonyl, halogenatedlower alkylcarbonyl, or cycloalkylcarbonyl; or R⁵ and R⁶ together withthe nitrogen atom to which they are attached form a 4-, 5-, 6- or7-membered saturated or unsaturated non-aromatic heterocyclic ringoptionally containing a further heteroatom selected from nitrogen,oxygen and sulfur, said heterocyclic ring being optionally mono-, di-,or tri-substituted, independently, with a group selected from the groupconsisting of lower alkyl, halogenated lower alkyl, oxo, dioxo andcyano; or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1, wherein R¹ is —C(O)—N(R⁵)R⁶.
 3. The compoundaccording to claim 1, wherein R¹ is —N(R⁵)R⁶.
 4. The compound accordingto claim 1, wherein R², R³ and R⁴ are each independently hydrogen,hydroxy or lower alkoxy.
 5. The compound according to claim 4, whereinR² is lower alkoxy.
 6. The compound according to claim 4, wherein R³ islower alkoxy.
 7. The compound according to claim 4, wherein R⁴ ishydrogen.
 8. The compound according to claim 1, wherein R⁵ is hydrogen,lower alkyl or halogenated lower alkyl.
 9. The compound according toclaim 1, wherein R⁶ is lower alkylsulfonyl, lower alkylcarbonyl orcycloalkylcarbonyl.
 10. The compound according to claim 1, wherein R⁵and R⁶ together with the nitrogen atom to which they are attached form a4-, 5-, 6- or 7-membered saturated or unsaturated non-aromaticheterocyclic ring optionally containing a further heteroatom selectedfrom a sulfur and oxygen, said heterocyclic ring being optionally mono-or di-substituted, independently, with a group selected from the groupconsisting of lower alkyl, halogenated lower alkyl, oxo, dioxo andcyano.
 11. The compound according to claim 10, wherein R⁵ and R⁶together with the nitrogen atom to which they are attached are selectedfrom the group consisting of pyrrolidine, pyrrolidin-2-one,4-methyl-pyrrolidin-2-one, 4-ethyl-pyrrolidin-2-one,3-methyl-pyrrolidin-2-one, 5-methyl-pyrrolidin-2-one,4-fluoro-methyl-pyrrolidin-2-one, pyrrolidine-2-carbonitrile,piperidine, piperidin-2-one, 4-methyl-piperidin-2-one,5-methyl-piperidin-2-one, 5,6-dihydro-1H-pyridin-2-one,thiazolidin-3-yl, 1,1-dioxo-1,2-thiazolidin-2-yl, 1,1-dioxo[1,2]thiazinan-2-yl, azetidine, azepan-2-one, oxazolidin-2-one,5-methyl-oxazolidin-2-one, 5-fluoromethyl-oxazolidin-2-one, and[1,3]oxazinan-2-one.
 12. The compound according to claim 1, selectedfrom the group consisting of:(RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-pyrrolidin-1-yl-methanone;(RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-thiazolidin-3-yl-methanone;(RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azetidin-1-yl-methanone;(SS)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carbonyl)-pyrrolidine-2-carbonitrile;1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one;(−)-(S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one;(+)-(R,R,R)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one;1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-piperidin-2-one;(RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-pyrrolidin-2-one; and1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 1, selected from the group consisting of:1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-ethyl-pyrrolidin-2-one;(RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5,6-dihydro-1H-pyridin-2-one;1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-azepan-2-one;(RS,RS,RS)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine;(RS,RS,RS)-3-(1,1-dioxo[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine;(S,S,S)-3-(1,1-dioxo-[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine;(SR)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;(RS,RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;(R)-1-((S,S,S)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one and(S)-1-((R,R,R)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one; or apharmaceutically acceptable salt thereof.
 14. The compound according toclaim 1, selected from the group consisting of:(S,S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;(R,R,R,R)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one;1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-piperidin-2-one;(RS,RS,RS)—N-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-propionamide;(RS,RS,RS)—N-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-butyramide; cydopropanecarboxylic acid((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-amide;(SR)-1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one;(RS,RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one and(S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one; or apharmaceutically acceptable salt thereof.
 15. The compound according toclaim 1, selected from the group consisting of: (R)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one;3-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-oxazolidin-2-one; 3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-[1,3]oxazinan-2-one; 1-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-pyrrolidin-2-one; 3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-fluoromethyl-oxazolidin-2-one; 1-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-3-methyl-pyrrolidin-2-one; and 3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-oxazolidin-2-one; or apharmaceutically acceptable salt thereof.
 16. The compound according toclaim 12, selected from the group consisting of:(RS,RS,RS)-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-thiazolidin-3-yl-methanone;(−)-(S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-piperidin-2-one;and1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;or a pharmaceutically acceptable salt thereof.
 17. The compoundaccording to claim 13, selected from the group consisting of:(RS,RS,RS)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5,6-dihydro-1H-pyridin-2-one;(S,S,S)-3-(1,1-dioxo-[1,2]thiazinan-2-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine; and(R)-1-((S,S,S)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 14, selected from the group consisting of:(S,S,S,S)-1-(2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-methyl-pyrrolidin-2-one;1-((RS,RS,RS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-piperidin-2-one;and(S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one; or apharmaceutically acceptable salt thereof.
 19. The compound according toclaim 15, selected from the group consisting of:(R)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one;and 3-((2RS,3RS,11bRS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-5-methyl-oxazolidin-2-one; or apharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 21. A method for the treatment ofnon-insulin dependent diabetes mellitus in a patient in need thereof,comprising administering to said patient a compound according to claim 1in an amount of from about 1 to 1000 mg per day.
 22. The methodaccording to claim 17, wherein the amount is from about 1 to 100 mg perday.